Robert J. Ignoffo

A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial.

In 1983, the Northern California Oncology Group (NCOG) instituted a randomized trial of intravenous (IV) versus intraarterial (IA) floxuridine (FUDR) administered via an implantable pump for patients with colorectal cancer metastatic to the liver. The study objectives were to compare the hepatic response rate, time to hepatic progression, and toxicity for the two treatment arms. The study design, which allowed patients failing IV FUDR to crossover to the IA arm, prevents a meaningful comparative analysis of survival. Patients with liver-only metastases (N = 143) were randomized, 76 to the IV arm and 67 to the IA arm, and 115 patients (65 IV, 50 IA) were fully evaluable. Of the 65 patients in the IV arm, 28 crossed over to IA treatment after failing IV FUDR. The dose-limiting toxicity of IV FUDR was diarrhea, whereas biliary toxicity limited both the dose and duration of IA FUDR therapy. Of the first 25 patients treated with IA FUDR at a dose of .3 mg/kg/day, 10 developed radiographically evident biliary strictures, and three developed permanent jaundice. With reduction of the initial IA FUDR dose to .2 mg/kg/day, and adoption of a policy of early dosage reduction, treatment interruption, or termination of therapy for persistent elevations in alkaline phosphatase, only two further cases of serious biliary toxicity occurred. However, 26 of the 50 IA FUDR patients ultimately had therapy terminated because of drug toxicity rather than disease progression. When compared with systemic infusion, infusion into the hepatic artery greatly enhanced the antitumor activity of FUDR against colorectal liver metastases. Although biliary toxicity is the most serious limitation of this form of therapy, biliary stricture and jaundice usually can be averted through careful monitoring of liver enzymes and early dosage reduction.

Toxicities and complications of implanted pump hepatic arterial and intravenous floxuridine infusion

Toxicities and complications were prospectively analyzed in patients with liver metastases receiving hepatic intra‐arterial (IA) and systemic intravenous (IV) floxuridine (FUDR) with the Infusaid (Intermedics‐Infusaid Corp., Norwood, MA) implantable pump. Among 55 patients treated with IA FUDR (0.3–0.1 mg/kg/day × 14, every 28 days), elevations in liver enzyme values, not attributable to disease progression, developed in 96% of patients. Serious biliary toxicity occurred in 31 patients (56%). In 16, biliary sclerosis was documented radiographically and was diagnosed clinically in 15 additional patients. Ten patients were hospitalized for biliary toxicity, including five who required cholecystectomy for acalculous cholecystitis. Because of the high reported incidence of serious gastroduodenal toxicity after IA FUDR infusion, our procedure for hepatic arterial cannulation was designed to eliminate misperfusion of the stomach and duodenum with drug; none of our patients experienced FUDR‐associated gastroduodenal ulceration or bleeding. Cyclic IV FUDR (0.05–0.15 mg/kg/day × 14, every 28 days) was administered to 31 participants of the Northern California Oncology Group trial (3L‐82‐1) of IV versus IA FUDR. Dose‐limiting toxicity was diarrhea. Serious toxicities were: protracted diarrhea (three), dermatitis (two), tear duct stenosis (two), and stomatitis (two). Three patients were hospitalized for toxicity. No hematologic or biliary toxicity occurred. The optimal route for treatment of hepatic metastases with continuous FUDR infusion has not yet been established. Systemic IV infusion has low morbidity, but preliminary response data need to be substantiated in controlled clinical trials before there can be widespread clinical application. High response rates for IA infusion have been previously documented. Morbidity due to acalculous cholecystitis and gastroduodenal ulceration can now be avoided. Despite significant progress in characterization of hepatobiliary toxicity, it remains dose‐limiting. Continuous IA FUDR infusion should remain under the aegis of dedicated treatment centers until standardized protocols with diminished toxicity are established.

Hepatic Arterial Chemotherapy for Colorectal Cancer Metastatic to the Liver

Hepatic metastases of colorectal origin are resistant to radiation and immunotherapy. Traditional intravenous chemotherapy produces responses in 10% to 30% of patients, and surgical resection is feasible in approximately 20% of patients who have a solitary or unilobar lesion. Infusion of cytotoxic agents into the hepatic artery, introduced 2 decades ago, is the most promising form of therapy for unresectable hepatic metastases. Fluorouracil, floxuridine, and mitomycin have been most commonly administered by hepatic arterial infusion. The recent development of a totally implantable pump has allowed prolonged ambulatory infusion of chemotherapeutic agents into the hepatic artery. We review the recent data on the pharmacology, therapeutic outcome, administration techniques, and complications of hepatic arterial chemotherapy. Future trials in this area should use uniform stratification variables and standardized criteria for evaluating response, time to progression, and survival.

Survey of topical oral solutions for the treatment of chemo-induced oral mucositis:

Purpose. The objectives of this study were (1) to describe the usage of topical oral solutions in patients experiencing chemotherapy-induced oral mucositis (CIOM); and (2) to survey the care of oral mucositis provided to patients by clinical oncology pharmacists in institutional settings. Methods. Surveys were distributed to institutional pharmacists in the US, who were asked to provide the components of their ‘magic mouthwash’. Other questions included whether an institutional mucositis management guideline is available and what is the involvement of clinical pharmacy in mucositis care. Results. Forty institutions returned surveys during the study period. The top five ingredients used to compound the magic mouthwash are diphenhydramine, viscous lidocaine, magnesium hydroxide/aluminum hydroxide, nystatin and corticosteroids. Most institutions administer the mouthwash every 4 hours (36%) or every 6 hours (36%). Of the surveyed institutions, 33% currently possess guidelines for the management of CIOM. Conclusions. Most institutions in the country formulate their topical solution, or magic mouthwash, with a variety of ingredients. There is a need to standardize the ingredients used to compound the magic mouthwash, in order to fully evaluate the efficacy of the solution to manage CIOM.

A guide to clinically relevant drug interactions in oncology

This paper presents an overview of new information on clinically relevant drug-drug interactions, particular focuses on negative drug interactions in oncology. We have generated a concise table of drug-drug interactions that provides a synopsis of the clinical outcome of the interaction along with a recommendation for management. We have also generated other tables that describe specific interactions with methotrexate and dosing guidelines for cytotoxic drugs in the presence of renal or hepatic dysfunction. Since warfarin is one of the non-anticancer drugs that is commonly used in cancer patients for the treatment and prevention of venous thromboembolism, its interactions with other anticancer drugs that have been reported in literatures were also reviewed in this paper. In general, drug interactions observed in cancer patients may be categorized into pharmacokinetic, pharmacodynamic and pharmaceutic interactions. Pharmacokinetic interactions involve one drug altering the absorption, distribution, metabolism, or excretion of another drug. Interpatient variability in the pharmacokinetic profile of many anticancer agents often complicates the predictability of the antitumor response and toxicities. Among four pharmacokinetic characteristics, drug interactions involving hepatic metabolism is probably the most common and important mechanism responsible for oncologic drug interactions. For example, several anticancer drugs including taxanes, vinca alkaloids, and irinotecan are known to be metabolized by cytochrome CYP3A4. Enzyme-inducing anticonvulsants have been shown to significantly decrease the plasma levels of these anticancer drugs, thereby compromising the anti-tumor effects. N ephrotoxicity or changes in hepatic function caused by some anticancer drugs (e.g., cisplatin, asparaginase) may also have an impact on the pharmacokinetics of the interacting agents. Pharmacodynamic interactions may occur when two or more drugs acting at a common receptor-binding site impact on the pharmacologic action of the object drug, without influencing the pharmacokinetics of each interacting agent. In clinical setting, a decrease of antitumor efficacy was observed in breast cell lines when gemcitabine or vinorelbine were used in combination with paclitaxel. On the other hand, a decreased incidence of thrombocytopenia was seen in patients receiving combination of carboplatin and palcitaxel compared to those receiving carboplatin alone. The third type of drug-drug interaction is known as pharmaceutic interaction. When one drug may alter the physical or chemical compatibility of another drug that utlimately leads to a change in appearance of the solution or a decrease of effectiveness of the drug due to drug inactivation or degradation.

Effect of telephone follow-up on the physical well-being dimension of quality of life in patients with cancer.

Objective. To evaluate the effect of telephone follow‐up on the physical wellbeing dimension of health‐related quality of life in patients with cancer.

Pharmacokinetics of methotrexate administered via the hepatic artery

SummaryThe pharmacokinetics of moderate doses of methotrexate administered via the hepatic artery were studied in ten patients with cancer metastatic to the liver. Intra-arterial methotrexate showed two-compartment characteristics with a clearance of 79 ml/min/m2 and an apparent volume of distribution of 21.2 l/m2 body surface area. The average half-life of the early phase was 1.9 h and the terminal half-life was 14.4 h. The data were not different from those observed in similar patients after IV administration of equivalent doses of methotrexate.

Adjusting Heparin Infusion Rates from the Initial Response to Activated Coagulation Time

A mathematical description of the dose-response curve of heparin to the activated coagulation time is applied retrospectively to 20 patients treated with continuous heparin infusion. The adjusted heparin dose was compared with a calculated prediction using the theoretical mathematical model. The main actual dose was 28 U/kg/h, and the mean predicted dose was 25.8 U/kg/h. The correlation coefficient was 0.862 (p30.05). These data are used to develop a dosing adjustment chart. Special considerations prior to using the calculation or dosing adjustment chart are discussed. The use of this model may allow the clinician to determine more rapidly a therapeutic heparin dosage than previous empiric approaches.

Current research on PONV/PDNV: Practical implications for today’s pharmacist

PURPOSE Guidelines have been constructed to optimize the management of patients at risk of developing postoperative nausea and vomiting or postdischarge nausea and vomiting (PONV/PDNV), including the 2002 American Society of Anesthesiologists (ASA) recommendations, the 2006 guidelines assembled by an American Society of PeriAnesthesia Nurses task force (ASPAN), and another set published in 2007 with the support of the Society for Ambulatory Anesthesia (SAMBA). The recommendations set forth are reviewed. SUMMARY Patient risk factors have been identified that are associated with higher incidences of PONV. For prophylaxis of PONV in high-risk patients, combinational and multimodal therapies with as many as three interventions, including a 5-HT(3)-based therapy and other antiemetic agents with different mechanisms of action, were advocated by guidelines and systematic reviews; specific pharmacotherapies and other interventions were recommended, as well as a treatment algorithm. The number of antiemetic agents prescribed should be appropriate for the individuals risk level, once again emphasizing the importance of patient risk stratification. Prophylaxis for PONV should be maintained throughout the period of risk. CONCLUSION Evidence from the Prospective Observational Study of Treatments, Outcomes, and Patterns of Care study indicates that the use of guideline recommended PONV and PDNV prophylactic treatments leads to improved outcomes.

Pharmaceutical care and the cancer patient

Purpose. The primary objective of this paper is to discuss pharmaceutical care of the oncology patient in the context of recent recommendations made by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and recent changes in Health Care Reform. Data Sources. We reviewed the literature through a MEDLINE search from 1985 to 1995. We searched the following terms: pharmaceutical care, cancer, patient, and pharmacist. We restricted the search to the English language. We also have incor porated several of our practice guidelines as examples of tools that can be used in the implementation of pharmaceutical care. We also focused on areas that the JCAHO guidelines specify as important pharma ceutical care issues in the cancer patient. Data Extraction. Within the framework of drug prescribing, drug administration, drug monitoring, and patient education, we have provided interven tions that may potentially improve outcomes in can cer patients. Data Synthesis. The advent of managed care will require that the pharmacist be more involved in the care and management of the cancer patient. This activity will necessitate that the pharmacist document the impact of interventions on patient outcomes. Although tumor response and survival are classic outcomes that are assessed in the cancer patient, other outcome indicators may be used to evaluate interventions made by the pharmacist. Conclusions. This review offers strategies for implementing pharmaceutical care in the cancer pa tient. Because we did not present study results on patient outcomes, it is unknown which of these proposed pharmacist interventions are important fac tors in the implementation of pharmaceutical care in this patient population. Although pharmaceutical care is the new paradigm in pharmacy practice, we must perform prospective studies to determine its value to the cancer community.